Drug-Induced Liver Injury Network Research Articles

Amiodarone and Dronedarone Causes Liver Injury with Distinctly Different Clinical Presentations

ObjectiveTo describe hepatotoxicity due to amiodarone and dronedarone from the DILIN and the US FDA’s surveillance database.MethodsHepatotoxicity due to amiodarone and dronedarone enrolled in the U.S. Drug Induced Liver Injury Network (DILIN) from 2004 to 2020 are described. Dronedarone hepatotoxicity cases associated with liver biopsy results were obtained from the FDA Adverse Event Reporting System (FAERS) from 2009 to 2020.ResultsAmong DILIN’s 10 amiodarone and 3 dronedarone DILIN cases, the latency for amiodarone was longer than with dronedarone (388 vs 119 days, p = 0.50) and the median ALT at DILI onset was significantly lower with amiodarone (118 vs 1191 U/L, p = 0.05). Liver biopsies in five amiodarone cases showed fibrosis, steatosis, and numerous Mallory-Denk bodies. Five patients died although only one from liver failure. One patient with dronedarone induced liver injury died of a non-liver related cause.Nine additional cases of DILI due to dronedarone requiring hospitalization were identified in the FAERS database. Three patients developed liver injury within a month of starting the medication. Two developed acute liver failure and underwent urgent liver transplant, one was evaluated for liver transplant but then recovered spontaneously, while one patient with cirrhosis died of liver related causes.ConclusionAmiodarone hepatotoxicity resembles that seen in alcohol related liver injury, with fatty infiltration and inflammation. Dronedarone is less predictable, typically without fat and with a shorter latency of use before presentation. These differences may be explained, in part, by the differing pharmacokinetics of the two drugs leading to different mechanisms of hepatotoxicity.

The ABC of Immune-Mediated Hepatitis during Immunotherapy in Patients with Cancer: From Pathogenesis to Multidisciplinary Management.

Immune-mediated hepatotoxicity (IMH) is not-so-rare complication during treatment with immune checkpoint inhibitors (ICIs). This narrative review aims to report the current knowledge on hepatic immune-related adverse events (irAEs) during immunotherapy from pathogenesis to multidisciplinary management. The majority of cases of IMH are asymptomatic and only a few patients may have clinical conditions. The severity of IMH is usually stratified according to Common Terminology for Clinical Adverse Events (CTCAE) criteria, but these scores may overestimate the clinical severity of IMH compared to the Drug-Induced Liver Injury Network (DILIN) scale. The differential diagnosis of IMH is challenging because the elevated liver enzymes can be due to a number of etiologies such as viral infection, autoimmune and metabolic diseases, liver metastases, biliary diseases, and other drugs. The cornerstones of IMH management are represented by withholding or delaying ICI administration and starting immunosuppressive therapy. A multidisciplinary team, including oncologists, hepatologists, internists, and emergency medicine physicians, is essential for the management of IMH.

ERAP-1 and ERAP-2 Variants in Liver Injury After COVID-19 mRNA Vaccination: A US Multicenter Study.

The aim of this study is to describe the presenting features, genetic factors, and outcomes of 23 adults who developed liver injury after coronavirus disease 2019 (COVID-19) mRNA vaccination. Patients with suspected COVID-19 vaccine hepatitis were enrolled into the Drug-Induced Liver Injury Network. Causality was assessed using the Drug-Induced Liver Injury Network expert opinion score. High-resolution HLA sequencing was undertaken using Illumina platform. Amongst the 16 high causality cases, median time to onset was 16 days, median age was 63 years, and 75% were female. The injury was hepatocellular in 75% with a median alanine aminotransferase of 497 U/L, and 37% had jaundice. An antinuclear antibody and smooth muscle antibody were detectable in 27% and 36%, but only 12% had an elevated immunoglobulin G level. During follow-up, 37% received a short course of corticosteroids, and 88% fully recovered by 6 months with no deaths observed. HLA alleles associated with autoimmune hepatitis were not overrepresented compared with controls, but an ERAP-2 variant (rs1263907) and the ERAP-1 Hap6 haplotype were significantly overrepresented in the high causality cases vs controls ( P = 0.026 and 5 × 10 -5 , respectively). Acute liver injury may arise within 8 weeks of COVID-19 mRNA vaccination that is generally mild and self-limited in most patients. The absence of an association with the AIH HLA alleles combined with the significant ERAP-2 and ERAP-1 Hap6 haplotype associations implicates a unique but very rare host immune response to vaccine-derived antigens in the pathogenesis of COVID-19 vaccine hepatotoxicity.

A study of the effect of antitubercular drugs on liver functions in newly diagnosed cases of tuberculosis during intensive phase of therapy in tertiary care hospital

Background: Antitubercular drugs are commonly associated with drug-induced liver injury (DILI), which can present as asymptomatic alterations in liver function test (LFT) to symptomatic hepatic injury and failure. Regular and frequent monitoring of LFT during intensive phase of therapy helps to identify early DILI and its complication. Aims and Objectives: The main objective was to evaluate the effects of antitubercular drugs on liver functions by early monitoring. Materials and Methods: A prospective observational study was conducted for 1 year among 97 newly diagnosed tuberculosis patients in tertiary care hospital. LFT was performed during baseline, at the end of 2nd week, and at end of intensive phase of treatment. Diagnosis of liver injury was based on DILI criteria and assessment of the clinical pattern of liver damage was done using “R value”. Results: Among 97 patients, 16 had experienced DILI and incidence was higher during the first visit. Aspartate aminotransferase (AST) and alanine aminotransferase were significantly altered during the first visit while AST and total bilirubin during the second visit. The number of parameters deranged was higher at the end of intensive phase than during the end of 2nd week. Cholestatic pattern (81.25 %) of liver injury was the most common type as per “R value”. According to DILI network severity index, the majority were categorized as “moderately-severe” and “moderate” during the first and second follow-up, respectively. Conclusion: The incidence of antitubercular drugs-induced liver injury was higher during the initial 2 weeks of treatment, but the derangement was more evident at the end of the intensive phase. Frequent and regular monitoring during the initial phase of treatment helps to detect early DILI which prevents the impending liver failure.

Characterization of drug-induced liver injury associated with drug reaction with eosinophilia and systemic symptoms in two prospective DILI registries.

Idiosyncratic drug-induced liver injury (DILI) associated with drug reactions with eosinophilia and systemic symptoms (DRESS) is poorly characterized among patients of Western countries. We aimed to comprehensively assess the clinical characteristics, outcomes, and causative agents in a prospective, well-vetted cohort of DILI patients with DRESS (DILI-DRESS). We identified 53 DILI-DRESS cases from the Spanish DILI Registry and the Latin American DILI Network. For comparison purposes, we defined a group of DILI patients (n = 881). DILI-DRESS cases were younger (47 vs. 53years, respectively; p = 0.042) and presented more frequently with cholestatic/mixed damage (p = 0.018). Most DILI-DRESS patients showed moderate liver injury, 13% developed severe damage, and only one patient (with hepatocellular injury due to anti-tuberculosis drugs) progressed to acute liver failure and died. DILI-DRESS cases showed a distinctive causative drug pattern compared to DILI cases. The most frequent drugs were carbamazepine (13%), anti-tuberculosis drugs (13%), amoxicillin-clavulanate (11%), and allopurinol and lamotrigine (7.6% each). Among all cases of DILI due to allopurinol and lamotrigine, 67% presented with a DILI-DRESS phenotype, respectively. Higher total bilirubin (TBL) levels at DILI recognition (odds ratio [OR] 1.23; 95% confidence interval [CI] 1.04-1.45) and absence of eosinophilia (OR 8.77; 95% CI 1.11-69.20) increased the risk for developing a severe-fatal injury in DILI-DRESS patients. DILI-DRESS patients have a more frequent cholestasis/mixed pattern of injury at presentation, with antiepileptics as distinctive causative drug class. Most of the lamotrigine and allopurinol cases present with this phenotype. Higher TBL levels and absence of eosinophilia at DILI recognition are markers of poor outcomes.

Vancomycin-Induced Liver Injury, DRESS, and HLA-A∗32:01

Intravenous vancomycin therapy can cause liver injury as well as "drug reaction with eosinophilia and systemic symptoms" (DRESS) syndrome. This study aimed to better define the clinical features and HLA associations of vancomycin-induced liver injury. To describe clinical, biochemical, and temporal characteristics of vancomycin-induced liver injury. Cases of liver injury with recent exposure to vancomycin who were enrolled in the US Drug-induced Liver Injury Network between 2004 and 2020 were assessed. Sequencing of HLA alleles was performed on stored blood samples. Among 1697 cases of drug-induced liver injury identified between 2004 and 2021, 9 (0.5%) were attributed to intravenous vancomycin. The 9 cases included 6 men, median age 60 years (range, 23-85 days), and treatment for 26 days (range, 1-34 days). The clinical presentation was DRESS syndrome in 8 patients, of whom 6 received corticosteroids. Liver injury varied from hepatocellular to cholestatic and from mild (n= 5) to fatal (n= 1). In survivors, liver injury and DRESS syndrome ultimately resolved. HLA typing demonstrated the HLA-A∗32:01 allele in 7 vancomycin cases (78%, all with DRESS syndrome), versus 1 of 81 cases (1.2%) exposed but not attributed to vancomycin, and 113 of 1708 cases (6.6%) without vancomycin exposure. The allele frequency in vancomycin cases was 0.44 compared with less than 0.04 in US populations. Vancomycin-induced liver injury is commonly associated with DRESS syndrome and linked to HLA-A∗32:01. HLA-A∗32:01 testing could be considered early to risk-stratify patients using long-term intravenous vancomycin therapy.

Clinical presentation, causative drugs and outcome of patients with autoimmune features in two prospective DILI registries.

Idiosyncratic drug-induced liver injury (DILI) with autoimmune features is a liver condition with laboratory and histological characteristics similar to those of idiopathic autoimmune hepatitis (AIH), which despite being increasingly reported, remains largely undefined. We aimed to describe in-depth the features of this entity in a large series of patients from two prospective DILI registries. DILI cases with autoimmune features collected in the Spanish DILI Registry and the Latin American DILI Network were compared with DILI patients without autoimmune features and with an independent cohort of patients with AIH. Out of 1,426 patients with DILI, 33 cases with autoimmune features were identified. Female sex was more frequent in AIH patients than in the other groups (p = .001). DILI cases with autoimmune features had significantly longer time to onset (p < .001) and resolution time (p = .004) than those without autoimmune features. Interestingly, DILI patients with autoimmune features who relapsed exhibited significantly higher total bilirubin and transaminases at onset and absence of peripheral eosinophilia than those who did not relapse. The likelihood of relapse increased over time, from 17% at 6 months to 50% 4 years after biochemical normalization. Statins, nitrofurantoin and minocycline were the drugs most frequently associated with this phenotype. DILI with autoimmune features shows different clinical features than DILI patients lacking characteristics of autoimmunity. Higher transaminases and total bilirubin values with no eosinophilia at presentation increase the likelihood of relapse in DILI with autoimmune features. As the tendency to relapse increases over time, these patients will require long-term follow-up.

Immunophenotyping to improve the mechanistic understanding of idiosyncratic drug-induced liver injury: clinical implications and future directions

The late event onset of a fraction of idiosyncratic drug-induced liver injury (DILI) cases and the link observed by genome-wide association studies (GWASs) of certain human leucocyte antigen (HLA) alleles with DILI due to specific drugs support the crucial role of the immune system (both innate and adaptive) in the pathogenesis of DILI. Recent advances in both flow and mass cytometry have allowed the profiling of all major immune cell types in a given sample. Therefore, determining the lymphocyte populations in samples from patients with DILI would facilitate the development of specific biomarkers for DILI diagnosis and prognosis. To date, a few studies have explored the immune landscape in DILI. In a recent study of leukocyte immunophenotyping using flow cytometry from the Spanish DILI Registry, an important role of adaptive immune response in DILI is suggested. DILI patients had significantly higher levels of T helper 1 (Th1) cells and activated helper and cytotoxic T cells than healthy controls. Furthermore, the increased expression of negative immune checkpoints and ligands in DILI patients could reflect a restoration of the immune homeostasis. Differences in the profile of cytokines in DILI patients from the Drug-Induced Liver Injury Network (DILIN) also suggest an involvement of both innate and adaptive immune systems in DILI development and prognosis. Moreover, several studies based on immunophenotyping of liver infiltrates showed a distinctive pattern of cellular infiltrates in patients with immune checkpoint inhibitors (ICIs)-DILI, with lower levels of plasma cells, CD20+ B cells and CD4+ T cells than in autoimmune hepatitis (AIH) patients. These pioneering studies highlight the importance of immunophenotyping for the mechanistic understanding of DILI. In this review, available data on immunophenotyping in DILI are gathered, and the potential clinical applications of cutting-edge, novel immunophenotyping techniques are discussed.

AASLD practice guidance on drug, herbal, and dietary supplement-induced liver injury.

AASLD practice guidance on drug, herbal, and dietary supplement-induced liver injury.

From the Editor’s Desk...

From the Editor’s Desk...

Liver Injury Associated with Turmeric—A Growing Problem: Ten Cases from the Drug-Induced Liver Injury Network [DILIN

BackgroundTurmeric is a commonly used herbal product that has been implicated in causing liver injury. The aim of this case series is to describe the clinical, histologic, and human leukocyte antigen (HLA) associations of turmeric-associated liver injury cases enrolled the in US Drug-Induced Liver Injury Network (DILIN). MethodsAll adjudicated cases enrolled in DILIN between 2004 and 2022 in which turmeric was an implicated product were reviewed. Causality was assessed using a 5-point expert opinion score. Available products were analyzed for the presence of turmeric using ultra-high-performance liquid chromatography. Genetic analyses included HLA sequencing. ResultsTen cases of turmeric-associated liver injury were found, all enrolled since 2011, and 6 since 2017. Of the 10 cases, 8 were women, 9 were White, and median age was 56 years (range 35-71). Liver injury was hepatocellular in 9 patients and mixed in 1. Liver biopsies in 4 patients showed acute hepatitis or mixed cholestatic-hepatic injury with eosinophils. Five patients were hospitalized, and 1 patient died of acute liver failure. Chemical analysis confirmed the presence of turmeric in all 7 products tested; 3 also contained piperine (black pepper). HLA typing demonstrated that 7 patients carried HLA-B*35:01, 2 of whom were homozygous, yielding an allele frequency of 0.450 compared with population controls of 0.056-0.069. ConclusionLiver injury due to turmeric appears to be increasing in the United States, perhaps reflecting usage patterns or increased combination with black pepper. Turmeric causes potentially severe liver injury that is typically hepatocellular, with a latency of 1 to 4 months and strong linkage to HLA-B*35:01.

S1203 When Is Suspected Drug Induced Liver Injury (DILI) Not DILI? An Analysis of Unlikely Cases from the U.S. Drug Induced Liver Injury Network (DILIN)

Introduction: The diagnosis of drug induced liver injury (DILI) is difficult as it is largely a clinical diagnosis of exclusion. To aid in diagnostic decision making, we reviewed cases enrolled in DILIN with an initial diagnosis of DILI that were ultimately adjudicated as unlikely with alternative etiologies accounting for the abnormal liver tests. Methods: The DILIN is an ongoing NIH observational trial in which hepatologists enrolled patients from 2004 to the present with a high suspicion of DILI. Cases were adjudicated by a panel of experts through a structured process and scored from 1 (definite DILI) to 5 (unlikely DILI). Cases that were scored at least probable DILI (1-3) were compared to unlikely DILI (5). Unlikely cases were further reviewed for salient features and trends over time. Results: From 9/04 to 12/21, 1916 cases were adjudicated; 134 (7%) were unlikely DILI. There were no demographic features to distinguish at least probable cases from unlikely cases. Unlikely cases more often had renal disease (18% vs 9%, p=0.005), HIV (7% vs 2% p< 0.001), hepatitis C (HCV) (12% vs 3% p< 0.001), and hepatitis B (5% vs 1 % p< 0.001). Unlikely DILI vs. true DILI was higher for brief latency between drug use and liver injury (< 1 week 9% vs 5%) or very long latency ( >24 weeks 28% vs 16%) p=0.002 overall. The most common alternative diagnoses for unlikely cases were autoimmune hepatitis (AIH) (20%) and HCV (20%) (Table). Among white patients, carriage frequency of two copies of HLA-DQA1*03:01 was greater among those with AIH (13%) compared to DILI (3%) and population controls (1%). Patients with unlikely DILI had greater all-cause (16% vs 7%, p< 0.001) and liver related mortality (10% vs 3%, p< 0.001). Unlikely DILI cases died within six months at a higher rate (14% vs 6%, p=0.004). Transplant rates, hospitalization, and duration of illness were similar. Conclusion: DILI is difficult to diagnose, even among experienced hepatologists. Demographic factors are not helpful in the initial diagnosis. Very short or very long latency between suspect drug and initial liver injury decreases likelihood of true DILI. HCV PCR testing is critical in presumed DILI. Genetic testing in white patients with AIH vs. DILI may be useful. Longitudinal follow up of patients with DILI is essential to refine the diagnosis, treat an alternative disease, and potentially absolve a medication presumed to have caused DILI. Table 1. - Alternative Diagnoses in 134 Unlikely DILI cases Diagnosis N % Comments Autoimmune hepatitis 27 20.1 The most common incorrectly implicated class of medications were antibiotics (9/27) followed by HDS products (8/27). Nearly all had a liver biopsy, but findings were neither diagnostic for DILI nor classic for AIH. Other common themes included 1) prevalent systemic immune mediated disease (systemic lupus erythematous, hypothyroidism, inflammatory bowel disease, etc.) in 8/27 cases; 2) negative or relatively low antinuclear antibody titers (< 1:80) which increased on follow up; 3) a response to steroids in 14/27 with six of these having a flare in enzymes after immunosuppression titration or withdrawal. Hepatitis C 27 20.1 Of the 24 that were acute cases, 17 were enrolled prior to 2011 and none since 2017. Most of these cases had negative HCV antibodies and were discovered to have a positive HCV viral load later in their clinical course. Three patients had prevalent detectable HCV virus which later cleared spontaneously on follow up. Gallstones/BiliaryDisease 18 13.4 Eight cases with biliary tract malignancy.Three cases with primary sclerosing cholangitis. Normal imaging in some patients who acutely passed a stone.No differences in the presence of stones (3.3% vs. 6.7% p=0.32), or ductal dilation (3.3% vs. 2.5% p=0.89) between unlikely DILI and probable and higher DILI cases. Hepatitis E 11 8.2 Diagnosis often delayed as test is a send-out in most centers. Sepsis 7 5.2 Frequently in Intensive Care Unit on multiple drugs and hypotensive. Other ( >20 diverse etiologies) 44 32.8 Etiologies included alcohol, myopathy, Epstein Barr virus, cytomegalovirus, nonalcoholic steatohepatitis, metastatic cancer, and granulomatous liver disease.

S1202 Drug-Induced Liver Injury (DILI) Ascribed to Non-Steroidal Anti-inflammatory Drugs (NSAIDs) in the USA: An Update With Genetic Correlations From the U.S. Drug-Induced Liver Injury Network (DILIN)

Introduction: NSAIDs are widely used throughout the world, mainly for management of chronic inflammatory and painful conditions. NSAIDs rarely cause idiosyncratic, non-dose dependent liver injury. Recent evidence from the US DILIN, as well as elsewhere, implicates host immune responses as central to pathogenesis of such idiosyncratic DILI. Previously, we reported the US DILIN experience with NSAID DILI for 2004-2013.1 Aim: To update our clinical experience and report on HLA and other genetic factors recently described as important in idiosyncratic DILI. Methods: The US DILIN, begun in 2004; is comprised of clinical sites [currently 7 in number], a data coordinating center, and the NIDDK. We enroll subjects with suspected DILI and follow them for at least 6 months.2 We adjudicate causality both with RUCAM, and RECAM3 and by a Delphic approach4 and grade severity from mild to fatal or requiring liver transplant.5 Between Sep 2004 and Mar 2022, we enrolled 2,626 subjects and adjudicated causality at 6 months in 2,498. Following adjudication, we identified 55 [41 (75%) women] as definitely [ >95%], highly likely [75-95%], or probably [51-74% likely] due to NSAIDs. Results: Diclofenac was the causative drug in 29/55 [53%] of cases, followed by celecoxib [7], ibuprofen [5], etodolac and meloxicam [4 each]. Median latency was 51 d. With the notable exceptions of meloxicam and oxaprozin [n=2], the type of liver injury was hepatocellular with median R 15-25. 4 subjects died within 6 mo of onset, and 2 others [1 each due to diclofenac and celecoxib] required liver transplants. 7 had chronic DILI at 6+ mo. HLA DRB1*03:01 was more frequent in those with NSAID DILI than in matched controls, and 6/10 had the ancestral AI extended haplotype. The likelihood of carrying the DRB1*04:03 allele increased with causality score confidence and with more severe DILI [p =0.006]. Conclusion: NSAID DILI is relatively rare in the US. The most common cause is diclofenac, which, if prescribed, should carry with it special warnings of risk and close observation, as in the package insert. The increased frequencies of HLA DRB1*03:01, an HLA type known to be associated with SLE and other auto-immune disorders, and the extended ancestral AI haplotype, suggests that immune-mediated responses are of central importance in pathogenesis.

S3229 A Case of Cholestatic Drug-Induced Liver Injury After Ashwagandha Root Supplementation

Introduction: Ashwagandha root is an ancient Indian Ayurvedic herbal medicine sometimes referred to as “Indian Winter cherry” or “Indian Ginseng,” that is growing in popularity for its purported benefits of weight loss, muscle building and stamina benefits, and cognition promoting effects. In vitro studies suggest possible benefits of ashwagandha to include muscle growth, exercise stamina, weight loss, hepatocellular carcinoma targeting, and others, but no large scale studies have been done to test for safety or adverse effects. Rare case reports of drug induced liver injury (DILI) related to ashwagandha have been documented. Case Description/Methods: 19-year-old male presented to our hospital with severe pruritus and new onset jaundice after starting Ashwagandha. Two weeks after starting he developed progressive pruritus without any noted rash. Five days after the onset of pruritis he noted jaundice with nausea and dark urine, no abdominal pain. Initial labs showed a total bilirubin 7.6, AP 149, ALT 144 and AST 74. He had imaging including MRI and CT scan which were unremarkable. He was discharged with prn hydroxyzine for itching and told his DILI would resolve with time. A month since discontinuing the ashwagandha supplements his pruritus and jaundice worsened and he arrived to our hospital for evaluation. He was treated with cholestyramine, ursodiol and antihistamines. His bilirubin ultimately nadired at 30. Was also started on low dose naltrexone, and discharged. Returned for short hospital stay with severe pruritis. His t. bili remained similar compared to prior at 29, with normal INR. He was started on low dose rifampin given persistent pruritus, with mild improvement, and ultimately discharged with close follow-up. Discussion: Ashwagandha root is a rare cause of cholestatic liver injury. The Drug Induced Liver Injury Network (DILIN) were able to identify five incidences of drug induced liver injury related to ashwagandha. The clinical course of our patient closely matches the six total cases described in the literature so far. Latency period of 2 weeks to the development of jaundice. He then had a prolonged course of cholestatic liver injury after discontinuing supplements that lasted several months. Ashwagandha-containing herbal medications can result in severe cholestatic liver injury, without the development of chronic DILI or progression to acute liver failure. This case report further re-enforces the importance of careful monitoring and awareness of our patients’ supplemental health products. Table 1. - Bilirubin and symptoms trend Days since Symptom onset 6 days 36 days 42 days 44 days 46 days 49 days 52 days 56 days 67 days Total Bilirubin Level 7.6 25 30 29 31.3 21.2 18 16.6 - Symptoms Jaundice/pruritis Worsening jaundice/pruritis/pale stools Persistent pruritis AMS vs. panic attack, persistent pruritis Mild improvement pruritis - Pruritis improving - Pruritis resolved, visible jaundice improving

S1218 Characteristics of Liver Injury Due to Azole Antifungal Drugs in the United States: Results From the Drug Induced Liver Injury Network (DILIN) Prospective Study

S1218 Characteristics of Liver Injury Due to Azole Antifungal Drugs in the United States: Results From the Drug Induced Liver Injury Network (DILIN) Prospective Study

Clinical features, outcomes, and HLA risk factors associated with nitrofurantoin-induced liver injury

Nitrofurantoin (NTF) is widely used for the treatment (short-term) and prevention (long-term) of urinary tract infections. We aimed to describe the clinical characteristics, outcomes, and HLA risk factors for NTF-induced liver injury (NTF-DILI) among individuals enrolled in the Drug Induced Liver Injury Network (DILIN). Seventy-eight individuals with definite, highly likely, or probable NTF-DILI were enrolled into DILIN studies between 2004-2020. HLA alleles were compared between NTF-DILI and three control groups: population (n= 14,001), idiopathic autoimmune hepatitis (n= 231), and non-NTF DILI (n= 661). Liver injury was hepatocellular in 69% and icteric in 55%. AST > ALT was more common in the 44 long-exposure (≥1 year) NTF-DILI cases than in the 18 short (≤7 days) and 16 intermediate (>7 to <365 days) exposure cases (73% vs. 33% vs. 50%, respectively, p= 0.018), as was ANA or SMA positivity (91% vs. 44% vs. 50%, respectively, p <0.001), and corticosteroid use (61% vs. 27% vs. 44%, respectively, p= 0.06). In long-term NTF-DILI, bridging fibrosis, nodularity or cirrhosis, or clinical and imaging evidence for cirrhosis were present in 38%, with massive or sub-massive necrosis in 20%. No one in the short-term exposure group died or underwent transplantation, whereas 7 (12%) patients from the other groups died or underwent transplantation. After covariate adjustments, HLA-DRB1∗11:04 was significantly more frequent in NTF-DILI compared to population controls (odds ratio [OR] 4.29, p= 1.15× 10-4), idiopathic autoimmune hepatitis (OR 11.77, p= 7.76× 10-5), and non-NTF DILI (OR 3.34, p= 0.003). NTF-DILI can result in parenchymal necrosis, bridging fibrosis, cirrhosis, and death or liver transplantation, especially with long-term exposure, and is associated with HLA-DRB1∗11:04. To mitigate against serious liver injury associated with NTF, regulators should revise the prescribing information and consider other mitigation strategies. Nitrofurantoin is a recognized cause of drug-induced liver injury (DILI). In this study consisting of a large cohort of well-phenotyped individuals with nitrofurantoin-induced liver injury, two distinct patterns of liver injury were identified: liver injury associated with short-term exposure, which is generally self-limiting, and liver injury associated with long-term exposure, which can lead to advanced fibrosis, cirrhosis and liver failure. HLA DRB1∗11:04 is a risk factor for liver injury due to long-term nitrofurantoin exposure. Our findings are important for regulators as well as physicians prescribing and pharmacists dispensing nitrofurantoin.

FRI002 - A report on the Australian Drug Induced Liver Injury Network: AusDILIN

FRI002 - A report on the Australian Drug Induced Liver Injury Network: AusDILIN

Incidence of Hepatitis E Infection in American Patients With Suspected Drug-Induced Liver Injury Is Low and Declining: The DILIN Prospective Study.

Hepatitis E virus (HEV) infection rarely causes icteric hepatitis, yet 10%-40% of adult Americans have serological evidence of previous infection. The aim of this study was to investigate the incidence, presentation, and outcome of acute and previous HEV infection in a large cohort of patients with suspected drug-induced liver injury (DILI). Serum samples from 2012 patients enrolled in the DILI Network were tested for anti-HEV immunoglobulin G (IgG). Those with detectable anti-HEV IgG underwent testing for anti-HEV IgM; those with detectable anti-HEV immunoglobulin m (IgM) were tested for HEV RNA. Anti-HEV IgG was detected in 407 (20%) patients and associated with increasing subject age and earlier year of enrollment. The median age of seropositive subjects was more than a decade higher than seronegative subjects (59.8 vs 48.7 years). The overall prevalence of anti-HEV declined from 22% (2004-2011) to 18% (2012-2019), suggestive of a cohort effect. The frequency of acute hepatitis E (median ALT = 1231 IU/L) also decreased from 3% (2004-2008) to 1.2% (2009-2013) to 0.6% (2014-2019). These results suggest that acute HEV infection is usually subclinical and was much more frequent in this cohort before 2004. Acute HEV infection accounts for less than 1% of suspected American DILI cases and is more frequent in older men. Previous HEV infection is also most commonly seen in older individuals. Clinicians should consider testing for unsuspected acute HEV infection in older adult patients with acute hepatocellular DILI and jaundice.

Reply.

Some people create their own storms and then get upset when it rains. —Anonymous We welcome the opinions of Balkrishna et al. on our multicenter study, which demonstrated a strong association of Tinospora cordifolia (Giloy) and autoimmune-like hepatitis.[1] The authors’ arguments supporting the “safety” of Giloy come from multiple preclinical sources; these unpublished, non-peer-reviewed work have misinterpreted published data on Giloy, or the lack of it, to suit their narrative. They claim that 40 ml/day of Giloy was akin to an “overdose” and provide a misleading citation. In fact, their own product page and that of the Ministry of Ayush Guidelines on coronavirus disease 2019 mention a maximum daily dose of 60–80 ml/day.[2, 3] Nonetheless, the authors’ claims are fictitious, as the efficacy and safety Giloy for the prevention or mitigation of any disease condition in humans is not yet identified through robust clinical trials. Contrary to what Balkrishna et al. argue, our patients consumed properly identified Giloy and authentically marketed Giloy-based products, which were advertised and recommended via public and private Ayush promotions. The presence of a pre-existing liver condition does not exclude Giloy liver injury, but enforces the importance of diagnosing herb-induced acute worsening of chronic liver disease, which is known to be associated with high mortality.[4] The type, concentration, effective dose, safety limits, and toxicity of bio-active phytocompounds in Giloy products should ideally be disclosed by the manufacturer. The authors lay out irrational arguments leveraged on their confirmation biases, in support of the safety of Giloy, using various preclinical rat models. However, it is well known that animal models have sizeable limitations for predicting toxicity in human clinical trials.[5] Balkrishna et al. appeal to ignorance regarding liver-toxic furano-diterpenoids, based on inaccurate citations that do not support their claims that these hepatotoxic compounds are lost during purification. The preparatory process for various Giloy-based formulations is not standardized. Nonetheless, they have missed the fact that Ayush Ministry guidelines explicitly state the use of aqueous-base extracted Giloy and not alcohol or chloroform processed decoctions.[3] The authors have misinterpreted our study, taken to strawman arguments and red-herring fallacies on cherry-picked aspects of chemical analysis, all the while trying to find closure for their labyrinthine, but flawed narrative on the safety of Giloy.[6] Giloy liver injury is a clinical diagnosis of exclusion, based on causality assessment and temporal association which we have succinctly proven. Finally, Balkrishna et al. willfully ignore the editorial on Giloy liver injury by experts from the US Drug-Induced Liver Injury Network, which re-assessed that Giloy can lead to liver injury with autoimmune features as well as worsen silent autoimmune hepatitis, which was also confirmed in our study.[7] Therefore, the evidence presented in our study strongly associates Giloy with observed hepatotoxicity and restates that non-evidence-based, poorly regulated traditional herbal products must be curbed. A “supervised” prescription is not the solution here, but awareness of the potential toxicity of Giloy, which has no proven clinical benefits. Our study demonstrates that preventing a modifiable disease is far more important than treating inadvertent complications. Nothing to report.

From the Editor’s Desk...

From the Editor’s Desk...